Many common pharmaceutical agents including many antibiotics, steroids, and certain vitamins are lipophilic, and poorly soluble (if at all) in water. This poor solubility creates difficulties in therapeutic administration, particularly parenteral administration, because bioavailability may be low and highly variable from patient-to-patient, high doses or numerous dosage units may be required per dose, there can be a slow onset of action, and performance is inconsistent. To solve these problems, efforts have been made to enhance solubility of insoluble pharmaceutical agents, for example by creating emulsions, encapsulating agents in liposomes or vesicles, and using surfactant micelles, but many of these efforts require complicated processing steps.
Common surfactants for drug solubilization include sodium lauryl sulfate, sodium sulphosuccinate, monodecyl trimethyl ammonium bromide, polysorbates, polyethylene glycols, and the like. However, many of these commonly used surfactants have toxic side effects such as hemolysis, damage to membrane permeability, changes to protein conformation, alteration of bioactivity of other compounds, and the like. Anionic and cationic surfactants are generally more toxic than non-ionic surfactants such as the polysorbate surfactants. Although polysorbates may have a better profile than anionic or cationic surfactant they can still exhibit significant side effects upon administration. These side effects are enhanced by the non-degradable nature of some surfactants. Thus, difficulties exist in developing safe parenteral formulations of poorly soluble and insoluble therapeutic agents.
For example, docetaxel is a poorly soluble anticancer drug that is supplied in the non-ionic surfactant polysorbate 80 (Tween® 80). For administration, the docetaxel-polysorbate 80 is diluted with a mixture of aqueous ethanol, and then into a saline or dextrose solution. Adding the aqueous ethanol to the polysorbate containing the docetaxel requires strong mixing to ensure complete dissolution of the polysorbate, thereby creating substantial amounts of foam that does not subside for long periods of time, e.g., more than 30 minutes, which can be inconvenient for direct administration or preparation of an administrative solution. In addition to these administrative difficulties, the polysorbate 80 has been found to cause hypersensitivity reactions and cumulative fluid retention in patients administered docetaxel.
Therefore, there is a need for more satisfactory surfactants, particularly surfactants having reduced side effects, to enhance the delivery of water-insoluble drugs.